Molecular docking study based on pharmacophore modeling for novel PhosphodiesteraseIV ınhibitors

Abstract

In this study pharmacophore modelling was carried out for novel PhosphodiesteraseIV (PDEIV) inhibitors. A pharmacophore-based virtual screening which resulted in 1959 hit compounds was performed with six chemical databases. The pharmacophore screening was proven to be successful in discriminating active and inactive inhibitors using a set of compounds with known activity obtained from ChEMBL database. Furthermore the Lipinskis rule of five was applied for physicochemical filtering of the hit molecules and this yielded 1840 compounds. Three docking software tools AutoDock 4.0 AutoDock Vina and Gold v5.1 were used for the docking process. All 1840 compounds and the known selective inhibitor rolipram were docked into the active site of the target protein. A total of 234 compounds with all three scoring values higher than those of rolipram were determined with the three docking tools. The interaction maps of 14 potent inhibitors complexed with PDEIV B and D isoforms have been analyzed and seven key residues (Asn 395 Gln 443 Tyr 233 Ile 410 Phe 446 Asp 392 Thr 407) were found to interact with more than 80?% of the potent inhibitors. For each one of the 234 hit compounds using the bound conformation with the highest AutoDock score the interacting residues were determined. 117 out of 234 compounds are found to interact with at least five of the seven key residues and these were selected for further evaluation. The conformation with the highest AutoDock score for each 117 compounds were rescored using the DSX scoring function. This yielded a total of 101 compounds with better score values than the natural ligand rolipram. For ADME/TOX calculations the FAF-Drugs2 server was used and 32 out of 101 compounds were found to be non-toxic.